DESCRIPTION: There is a pressing need to develop new antimalarials. Drug resistant strains continue to compromise the effectiveness of known agents and relative to other worldwide diseases the international community has devoted less attention to developing a broad arsenal of drugs to treat malaria. The long term objectives of the proposed research program are to create nontoxic antimalarial drugs based on the natural product artemisinin. The Avery laboratory has been engaged in the study of artemisinin and its derivatives for a number of years. The great deal of preliminary research and thought reflected in this proposal is of an excellent quality. A wide range of structural types based on the artemisinin skeleton have been or will be prepared. In fact, a complete study of the effect of substituents at each of the sites of this skeleton is outlined. Application of computer aided modeling techniques to explore the structure-toxicity relationship is also suggested. Data on the issue of the neurotoxicity associated with the artemisinin skeleton has been obtained. Comparison of toxicity models with activity models should ultimately aid in the design of simplified structures with low predicted toxicity, and high predicted antimalarial activity. A high level of significance can be placed on this project because the mode of action of the artemisinin class appears to be unique in comparison to other antimalarials.